Despite overall improvements in infant mortality in recent decades, morbidity from birth asphyxia remains largely unchanged and causes a significant burden to society. Inducing hypothermia within 6 hours of birth is an accepted treatment for neonates that suffer hypoxic-ischemic (HI) brain injury, but it remains underutilized worldwide. Moreover, neurologic and cognitive disabilities persist into late childhood in many of those treated. Thus, a critical need persists to find other therapies to be used alone or with hypothermia. In a neonatal animal model of HI that results in cerebral injury similar to that observed in term newborns, we found in preliminary experiments that injection of the naturally occurring chemoprotectant sulforaphane or the synthetic triterpenoid CDDO-EA after HI injury provided more robust neuroprotection than ten other candidate drugs previously tested in this model. Remarkably, this protection exceeded that observed when hypothermia was initiated at a clinically relevant delay of 3-4 hours after HI. In adult models of stroke and brain trauma, sulforaphane and CDDO-EA cause translocation of the transcription factor Nrf2 to the nucleus, where it binds to the antioxidant response element on promoters of genes of multiple Phase II antioxidant and defense enzymes. Nrf2 activators are attractive neuroprotective candidates for neonatal HI because of their multipotent action in upregulating a network of antioxidant systems and downregulating the inflammatory response. In Aim 1, we will test various doses of sulforaphane and CDDO-EA in neonatal animals. Using the dose and drug with optimal neuroprotection, we assess a broad therapeutic window for neuroprotection with a detailed stereologic analysis of surviving neurons in the vulnerable sensorimotor cortex, putamen, sensory thalamus, and hippocampal CA3 regions. We will also assess neurologic deficits and cognitive function. Thus far, preliminary data indicate robust neuroprotection in males and females when the activators are administered 5 min or 1 h after HI. The neuroprotection is associated with behavioral improvements. In Aim 2, we will examine the ability of Nrf2 activators, in the setting of reoxygenation of the neonatal brain, to stimulate nuclear translocation of Nrf2 and to upregulate antioxidant enzymes that are critical for glutathione synthesis and its antioxidant activity. Furthermore, we will determine the degree to which the drug attenuates glutathione depletion, a critical antioxidant in neonatal HI, and whether treatment blunts markers of oxidative stress and reduces neuroinflammation. Because neurons in immature brain die by different forms of programmed necrosis and apoptosis in a region-specific manner, we will investigate whether Nrf2 activators ameliorate specific forms of cell death signaling. Because therapeutic hypothermia is becoming the standard of care, in Aim 3 we will test whether Nrf2 activators augment the efficacy of hypothermia. Data obtained from these detailed preclinical studies in accordance with the STAIR and RIGOR guidelines are expected to form the basis for possible translation of Nrf2 activators as a sole therapeutic or as an adjunct therapy to hypothermia for neonatal HI.